The Early versus Later Intervention Trial with Estradiol (ELITE) is a randomized, double-blind, placebo- controlled, serial arterial imaging (carotid artery intima-media thickness) trial designed to test the timing hypothesis which posits that there is a differential effect of hormone therapy (HT) on atherosclerosis progression according to when HT is initiated in relation to menopause. ELITE is a 2x2 factorial trial in which healthy postmenopausal women without pre-existing cardiovascular disease were randomized to 172-estradiol or placebo according to their time since menopause, <6 years or >10 years. Since initially proposed 6 years ago, the scientific evidence for the timing hypothesis has grown substantially. ELITE was randomized ahead of schedule, the dropout rate is lower than initially projected, compliance with the study intervention remains >94% and adverse effects are low. This Renewal Application is submitted for 2 specific purposes: 1) to broaden the trial imaging end point to subclinical atherosclerosis of the coronary arteries through contrast and non-contrast cardiac computed tomography to validate and extend recent findings that HT potentially reduces coronary artery disease in young postmenopausal women; and, 2) to extend the intervention period of ELITE to sufficiently increase power to detect a smaller treatment interaction between time since menopause strata than originally designed since ELITE remains the only randomized controlled trial specifically designed to test the timing hypothesis. To determine whether the biologic response to 172-estradiol is different in younger versus older postmenopausal women (defined as time since menopause) remains the long-term and primary goal of this trial. PUBLIC HEALTH RELEVANCE: With the growing number of women entering menopause (approximately 50% of U.S. women will be >45 years old by 2015) and with the introduction of new hormonal products into the marketplace, use of postmenopausal hormone therapy (HT) will continue. Therefore, understanding the effect of HT on the progression of subclinical atherosclerosis, especially in young postmenopausal women who are likely to initiate these products for menopausal symptoms (primarily for flushing since there are no comparably effective alternatives) continues to be an important and timely public health issue.